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Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells

BACKGROUND: Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potenti...

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Autores principales: Punia, Reenu, Raina, Komal, Agarwal, Rajesh, Singh, Rana P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578506/
https://www.ncbi.nlm.nih.gov/pubmed/28859099
http://dx.doi.org/10.1371/journal.pone.0182870
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author Punia, Reenu
Raina, Komal
Agarwal, Rajesh
Singh, Rana P.
author_facet Punia, Reenu
Raina, Komal
Agarwal, Rajesh
Singh, Rana P.
author_sort Punia, Reenu
collection PubMed
description BACKGROUND: Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients. PURPOSE: In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC) cells. STUDY DESIGN: During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin. METHODS: The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR. RESULTS: The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin—doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on doxorubicin influx and efflux was mediated through downregulation of MDR1 treansporter in NSCLC cells. CONCLUSION: These findings suggested that acacetin augments the cytotoxicity of doxorubicin at lower concentrations in lung cancer cells. Their combination leads to more retention of doxorubicin in the cells by modulating drug trasporter and thus enhances its therapeutic potential.
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spelling pubmed-55785062017-09-15 Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells Punia, Reenu Raina, Komal Agarwal, Rajesh Singh, Rana P. PLoS One Research Article BACKGROUND: Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients. PURPOSE: In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC) cells. STUDY DESIGN: During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin. METHODS: The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR. RESULTS: The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin—doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on doxorubicin influx and efflux was mediated through downregulation of MDR1 treansporter in NSCLC cells. CONCLUSION: These findings suggested that acacetin augments the cytotoxicity of doxorubicin at lower concentrations in lung cancer cells. Their combination leads to more retention of doxorubicin in the cells by modulating drug trasporter and thus enhances its therapeutic potential. Public Library of Science 2017-08-31 /pmc/articles/PMC5578506/ /pubmed/28859099 http://dx.doi.org/10.1371/journal.pone.0182870 Text en © 2017 Punia et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Punia, Reenu
Raina, Komal
Agarwal, Rajesh
Singh, Rana P.
Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells
title Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells
title_full Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells
title_fullStr Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells
title_full_unstemmed Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells
title_short Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells
title_sort acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578506/
https://www.ncbi.nlm.nih.gov/pubmed/28859099
http://dx.doi.org/10.1371/journal.pone.0182870
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